DESC:Field of the Invention:
The present application relates to an improved process for the preparation of
Varenicline, which is represented by the following structural formula-1.
5
Formula-1
Background of the Invention:
Varenicline, as a salt of L-tartaric acid is approved in USA for the 10 treatment of smoking
addiction, is available in the market with the brand name CHANTIX® developed by Pfizer
in the form of tablet. Varenicline L-tartrate (Formula-1) is the international commonly
accepted name for 7,8,9,10-tetrahydro-6H-6,10-methano pyrazino[2,3-h][3] benzazepine,
(2R, 3R)-2,3-di hydroxybutanedioate (1:1).
15 The patent US6410550B2. first disclosed Varenicline free base and pharmaceutically
acceptable salts. The US’550 disclosed a process for preparation of varenicline free base
and its hydrochloride salt. The process involves reaction of 10-aza-tricyclo[6.3.1.02,7]do
deca-2(7),3,5-triene hydrochloride salt with trifluoroacetic anhydride in pyridine to obtain 1-
(10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone.The obtained
20 compound reacted with nitric acid in trifluoromethane sulfonic acid to give 1-(4,5-dinitro-
10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone, which is
hydrogenated with Pd(OH)2 under hydrogen gas in methanol to obtain 1-(4,5-di amino -10-
aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone. The obtained
compound is reacted with glyoxal sodium bisulphate, followed by deprotection by using
25 sodium carbonate to provide varenicline as free base. The obtained varenicline free base was
converted to its hydrochloride salt.
The US68090927B2 reported varenicline L-tartrate salt and its polymorphs and
processes thereof.
3
The US20080275051A1 reported a process for preparation of varenicline free base
by reacting 1-(4,5-diamino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-tri
fluoro-ethanone with aqueous glyoxal in a protic alcoholic solvent, the obtained compound
was deprotected to obtain varenicline free base.
The US2012004239A1 reported a one pot process for preparation 5 of varenicline free
base.
There are various processes reported for varenicline free base and salts thereof using
different solvents, reagents.
Based on the prior art processes draw backs, there is a need for providing an
10 improved process for the preparation of varenicline L-tartrate, which involves simple
experimental procedures, well suited to industrial production, which avoids the use of
column chromatography purification, and which affords high pure varenicline L-tartrate.
The present invention provides an improved process for preparation of Verenicline
free base and salts thereof, which is efficient, industrially viable and cost effective.
15 Brief Description :
The first aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-1.
The second aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-8.
20 The third aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-10.
The fourth aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-1.
25 Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of crystalline form-B of compound of formula-1
according to example-5
Detailed Description:
30 As used herein the term “suitable solvent” used in the present invention refers to
“hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane,
4
cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as
dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene
glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,
diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl
ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as 5 methyl acetate, ethyl
acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as
dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), Nmethylpyrrolidone
(NMP) and the like; “chloro solvents” such as dichloromethane,
dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as
10 acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as
acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol,
ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-
fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol,
diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol
15 monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar
solvents” such as water or mixtures thereof.
As used herein the present invention the term “suitable base” refers to inorganic or
organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate,
potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as
20 sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as
sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal
alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium
ethoxide, sodium tert.butoxide, potassium tert-butoxide, lithium tert-butoxide and the like;
alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the
25 like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like;
and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, diisopropyl
ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine
(DMAP), N-methyl morpholine (NMM), or mixtures thereof.
5
The term “reducing” agent used in the present invention refers suitable reducing reagents are
selected from Lithium aluminium hydride, sodium borohydride, BF3 etherate solution, Pd/C,
Ray-nickel;
The term “protecting” agent used in the present invention refers to a suitable protecting
reagents that are selected selected from di-tert-butyl dicarbonate, 5 chlorobenzyl formate,
benzylbromide, benzylchloride, acetylchloride, fluorenylmethyloxycarbonyl chloride; The
term “phase transfer catalyst (PTC)” used in the present invention refers are selected from
triethylbenzyl ammonium chloride, tetrabutyl ammoniumbromide, tetrabutyl ammonium
chloride, tetrabutyl ammonium acetate, methyl tributyl ammonium chloride, tetrabutyl
10 ammonium hydroxide, tributylbenzylammonium chloride;
The first aspect of the present invention provides an improved process for the
preparation of compound of formula-1,
15 Formula-1
comprising of:
a) Reacting compound of formula-2
Formula-2
20 with compound of formula-3
Formula-3
in presence of magnesium, in suitable solvent to provide compound of formula-4,
25 Formula-4
6
b) oxidising the compound obtained in step-a) with suitable reagent, solvent to provide
compound of formula -5,
Formula-5
c) reacting the compound obtained in step-b) with suitable reagent, 5 solvent in presence of
phase transfer catalyst to provide compound of formula-6,
Formula-6
further reacting the compound of formula-6 in-situ with benzylamine in presence of sodium
10 borohydride to provide compound of formula-7,
Formula-7
d) debenzylating the compound obtained in step-c) in presence of suitable reagent, solvent
15 to provide compound of formula-8 or free base,
HCl
Formula-8
e)protecting the compound obtained in step-d) with trifluoroacetic anhydride in presence of
20 suitable base, solvent to provide compound of formula-9, further reacting the compound of
formula-9 in-situ with nitration mixture to provide compound of formula-10,
Formula-10
7
f)reducing the compound obtained in step-e) with palladium catalyst under hydrogen gas
atmosphere in suitable solvent to provide compound of formula-11, further reacting the
compound of formula-11 in situ with glyoxal solution in water to provide compound of
formula-12,
5
Formula-12
g)deprotecting the compound obtained is step-f) with inorganic base in a suitable solvent to
provide compound of formula-13,
10 Formula-13
h)treating the compound obtained in step-g) with tartaric acid in a suitable solvent to obtain
compound of formula-1 or 1a ,
Formula-1a
15 i)optionally purifying the compound obtained in step-h) with suitable base in suitable solvent
to provide varenicline, further converting to tartrate salt of compound of formula-1.
Wherein in step-a) the suitable solvent is selected from chloro solvents, ether solvents, or
any mixture thereof; preferably : tetrahydrofuran, ether;
wherein in step-b) the suitable solvent is selected from chloro solvents, ether solvents,
20 ketone solvents, ester solvents or any mixture thereof; preferably acetone; the suitable
oxidising agent is osmium tetroxide; other reagent is N-methylmorpholine N-oxide in
butanol solution;
wherein in step-c) the suitable reagent is sodium periodate; the suitable phase transfer
catalyst is selected from triethylbenzyl ammonium chloride, tetrabutylammoniumbromide,
25 tetrabutyl ammonium chloride, tetrabutyl ammonium acetate, methyltributyl ammonium
8
chloride, tetrabutyl ammonium hydroxide, tributyl benzyl ammonium chloride; the suitable
solvent is selected from chloro solvents, ether solvents, polar aprotic solvents, ester solvents
or any mixture thereof; preferably dichloromethane;
the suitable regents for cyclisation is benzylamine; reducing agent is sodium borohydride,
triacetoxy 5 sodiumborohydride;
wherein in step-d) the suitable solvent is selected from chloro solvents, ether solvents, polar
aprotic solvents, polar solvents, alcoholic solvents, ester solvents, Con.HCl or any mixture
thereof; preferably methanolic HCl; the suitable palladium catalyst is selected from Pd(OH)2,
Pd[P(PPh3)]4 , PdCl2, Pd/C; Preferably Pd(OH)2, Pd/C;
10 Optionally the other suitable reagent for debenzylation is ethylchloroformate, methyl chloro
formate, chloroethyl chloro formate; suitable solvents is selected from toluene, benzene,
xylene, methanol, ethanol;
wherein in step-e) the suitable solvent is selected from chloro solvents, ether solvents, polar
aprotic solvents, ester solvents, or any mixture thereof; preferably dichloromethane; the
15 suitable base is selected from organic bases, inorganic base; preferably triethylamine;
protecting agent is trifluoroacetic anhydride; the suitable nitration mixture is trifluoro
methane sulphonic acid, nitric acid or Sulfuric acid, nitric acid;
wherein in step-f) the suitable solvent is selected from chloro solvents, ether solvents, polar
aprotic solvents, ester solvents, alcohol or any mixture thereof; preferably ethyl acetate;
20 the suitable palladium catalyst is selected from Pd(OH)2, Pd[P(PPh3)]4 , PdCl2, Pd/C;
Preferably Pd(OH)2, Pd/C;
wherein in step-g) the suitable solvent is selected from chloro solvents, ether solvents, polar
aprotic solvents, ester solvents, alcohol or any mixture thereof; preferably methanol;
The suitable base is inorganic base; preferably sodium carbonate;
25 wherein in step-h) the suitable solvent is selected from chloro solvents, ether solvents, polar
aprotic solvents, ester solvents, alcohol or any mixture thereof; preferably methanol;
wherein in step-i) the suitable solvent is selected from chloro solvents, ether solvents, polar
aprotic solvents, ester solvents, alcohol or any mixture thereof; preferably dichloromethane,
methanol; the suitable base is selected from inorganic base; preferably sodium hydroxide;
30
9
Preferred embodiment of the present invention provides an improved process for the
preparation of the compound of formula-1,
Formula-1
5 comprising of:
a)reacting compound of formula-2
Formula-2
with compound of formula-3
10
Formula-3
in presence of magnesium in tetrahydrofuran to provide compound of formula-4,
Formula-4
15 b)oxidising the compound obtained in step-a) with osmium tetroxide, in presence of
butanolic solution of N-methylmorpholine N-oxide, in acetone to provide compound of
formula -5,
Formula-5
20 c)reacting the compound obtained in step-b) with sodium periodate in presence of triethyl
benzyl ammonium chloride in dichloromethane to provide compound of formula-6,
Formula-6
10
further reacting the compound of formula-6 in-situ with benzylamine in presence of sodium
borohydride, acetic acid to provide compound of formula-7,
Formula-7
d)debenzylating the compound obtained in step-c) in presence of 5 palladium hydroxide in
methanolic HCl to provide compound of formula-8,
Formula-8
10 e)protecting the compound obtained in step-d) with trifluoroacetic anhydride in presence of
triethylamine in dichloromethane to provide compound of formula-9, further reacting the
compound of formula-9 in-situ with nitric acid in trifluoromethane sulfonic acid, to provide
compound of formula-10. (or)
Optionally isolating compound of formula-9 reacting with nitricacid in trifluoromethane
15 sulfonic acid to provide compound of formula-10,
Formula-10
f)reducing the compound obtained in step-e) with palladium hydroxide catalyst under
hydrogen gas atmosphere in ethyl acetate to provide compound of formula-11, further
20 reacting the compound of formula-11 in situ with glyoxal solution in water to provide
compound of formula-12,
Formula-12
g)deprotecting the compound obtained is step-f) with sodium carbonate in methanol to
25 provide compound of formula-13,
11
Formula-13
h)treating the compound obtained in step-g) with tartaric acid in methanol to provide
compound 5 of formula-1 or 1a,
Formula-1a
i) optionally purifying the compound obtained in step-h) by basification with sodium
hydroxide in dichloromethane followed by converting to tartaric acid salt of varenicline.
10
The second aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-8
HCl
Formula-8
15 Comprising of,
a)reacting the compound of formula-5 with sodiumperiodate in presence of triethyl benzyl
ammonium chloride in dichloromethane to provide compound of formula-6,
Formula-6
20 further reacting the compound of formula-6 in-situ with benzylamine in presence of sodium
borohydride to provide compound of formula-7,
Formula-7
12
b)debenzylating the compound obtained in step-a) in presence of palladium hydroxide in
methanolic HCl to provide compound of formula-8,
HCl
Formula-8
Other preferred embodiment of the present invention is debenzylation 5 of compound of
formula-7 with ethylchloroformate in toluene at suitable temperature, followed by methanol
to obtain compound of formula-8. The suitable temperature is 25-120°C;
The third aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-10.
10
Formula-10
Comprising of;
a)protecting the compound of formula-8 with trifluoroacetic anhydride in presence of tri
ethylamine in dichloromethane to provide compound of formula-9, further reacting the
15 compound of formula-9 in-situ with nitricacid in trifluoromethane sulfonic acid to provide
compound of formula-10 (or)
optionally isolating compound of formula-9 reacting with nitricacid in trifluoromethane
sulfonic acid to provide compound of formula-10.
20
Formula-10
The fourth aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-1(one pot process)
25 Formula-1
13
Comprising of:
a)reducing the compound of formula-10 with palladium hydroxide catalyst under hydrogen
gas atmosphere in ethyl acetate to provide compound of formula-11, further reacting the
compound of formula-11 in-situ with glyoxal solution in water to provide compound of
5 formula-12,
Formula-12
b)deprotecting the compound obtained is step-a) with sodium carbonate in methanol to
provide compound of formula-13,
10
Formula-13
c)treating the compound obtained in step-b) with tartaric acid in methanol to provide
compound of formula-1 or 1a.
15 Formula-1a
Varenicline tartrate salt and its polymorphs produced by the present invention can be
further micronized or milled to get the desired particle size to achieve desired solubility
profile based on different forms of pharmaceutical composition requirements. Techniques
that may be used for particle size reduction include, but not limited to ball, roller and hammer
20 mills, and jet mills. Milling or micronization may be performed before drying, or after the
completion of drying of the product.
PXRD analysis of Varenicline tartrate was carried out using BRUKER D8
ADVANCED/AXS X-Ray diffractometer using Cu Ká radiation of wavelength 1.5406 A°
and continuous scan speed of 0.03°/min. IR spectra were recorded on a Perkin-Elmer FTIR
25 spectrometer.
14
The process of the present invention can be represented schematically as follows:
5
The process described in the present invention was demonstrated in examples
illustrated below. These examples are provided as illustration only and therefore should not
be construed as limitation of the scope of the invention.
10 Examples:
Example-1: Preparation of the compound of formula-5.
A round bottom flask was charged with compound of formula-3 (50 g; freshly distilled),
added compound of formula-2 (100 g) at -5 to 5°C and stirred for 15 min.
Another round bottom flask was charged with magnesium turnings (20 g), tetrahydrofuran
15 (200 mL) under nitrogen atmosphere stirred for 15 min, charged iodine (0.2 g) and heated to
60-70°C. To the reaction mixture slowly added the mixture of 1-bromo-2-fluorobenzene (4.2
15
g), 1,2-dibromoethane (0.78 g) at 60-70°C. The reaction mass was cooled to 20-30°C, slowly
added the first reaction mixture at reflux condition (below 75°C) for 2-3 hr, stirred at 65-
75°C for 6-7 hr. The reaction mixture was cooled to 20-30°C, quenched with cooled water
(500 mL), added HCl (150 mL) and stirred for 15 min. The reaction mixture was charged
with ethyl acetate (500 mL) and separated the layers, the aqueous layer 5 was extracted with
ethyl acetate (2x100 mL). The combined organic layer was washed with sodium carbonate
(16 g in 200 mL) and dried over sodium sulphate. The organic layer was distilled off
completely and co-distilled with acetone (25 mL) to obtain residue. The obtained residue was
charged with acetone (200 mL) and N-methyl morpholine-N-oxide (154 g) stirred for 15 min.
10 A solution of osmium tetroxide (0.2 g in n-butanol 5 mL) was added to the above reaction
mixture and stirred at 60-70°C for 4 hr. The reaction mixture was cooled to 5-15°C stirred for
2 hr, filtered the obtain solid and washed with acetone (100 mL), dried to get the title
compound.
Yield: 38.5 g
15 Example-2: Preparation of the compound of formula-8.
A round bottom flask was charged with a compound of formula-5 (100.0 g), water (2 L),
dichloromethane (1 L) stirred for 15 min. The reaction mixture was cooled to 5-15°C added
sodiumperiodate (145 g), benzyltriethylammonium chloride (11.9 g) and stirred for 4 hr at
15-25°C. The both layers were separated, the aqueous layer was extracted with dichloro
20 methane (2x100 mL), the combined organic layer was dried over sodium sulphate.
Another round bottom flask was charged with sodium borohydride (66.5 g), dichloro
methane (1 L) and cooled to 0-5°C, slowly added acetic acid (343.3 g) followed by benzyl
amine (64 g) and stirred for 30 min. The reaction mixture was cooled to 0-10°C, added the
above dried organic solution slowly and stirred for 3 hr at 25-35°C. The reaction mixture pH
25 was adjusted to 8-9 with sodium hydroxide solution (100 g in 400 mL water), charged water
(500 mL) and separated the layers. The aqueous layer was extracted with dichloromethane
(200 mL x 2), the combined organic layer was washed with water (200 mL x2) and dried
over sodium sulphate. The organic layer was distilled off completely and co distilled with
methanol (50 mL). The crude compound was charged with methanol (500 mL), charcoal (5 g)
30 stirred for 15 min. Filtered the reaction mass, washed with methanol (50 mL) and adjusted
16
pH of the filtrate solution to 2.5-3.5 with methanolic HCl. The reaction mixture was charged
with palladium hydroxide (15 g), stirred under hydrogen gas pressure 5.0-6.0 kg /cm2 for 12
hr. The reaction mixture was filtered through hyflow, washed with methanol (50 mL).
Methanol was distilled off completely from the filtrate, co distilled with acetone (50 mL) and
stirred in acetone (200 mL) for 60 min. Filtered the obtained solid, 5 washed with acetone (50
mL) and dried to get the title compound.
Yield: 71.5 g.
Example-3: Preparation of the compound of formula-10.
A round bottom flask was charged with dichloromethane (250 mL), compound of formula-8
10 (50 g) at 25-35°C and stirred for 10 min. The reaction mixture was cooled to 0-10°C added
triethyl amine (62.5 g), trifluoroacetic anhydride (65 g) and stirred for 4 hr at 25-35°C. The
reaction mixture was charged with water (250 mL), separated the layers. Aqueous layer was
extracted with dichloromethane (2x500 mL) . The combined organic layer was washed with
dil HCl (2x50 mL), brine solution (50 mL) and dried over sodium sulphate.
15 Another round bottom flask was charged with trifluoromethane sulphonic acid (175.0 g),
dichloro methane (200 mL), cooled to -5 to 5°C slowly added nitricacid (40 g) and stirred.
To the reaction above nitration mixture, the dried organic layer was slowly added at -5 to 5°C
and stirred for 3 hr at 25-35°C. The reaction mixture was quenched with water (250 mL) at 0-
10°C, stirred at 20-30°C and separated the both layers. The aqueous layer was extracted with
20 dichloromethane (2x50 mL), the combined organic layer was washed with sodium
bicarbonate solution (50 mL). The organic layer was dried over sodium sulfate and distilled
off completely, co-distilled with ethyl acetate (12.5 mL). The crude compound was charged
with ethyl acetate (50 mL) and heated to 50-60°C stirred for 1 hr. The reaction mixture was
cooled to 5-15°C, filtered the obtained solid and dried to get the title compound.
25 Yield: 55.36 g.
Example-4: Preparation of the compound of formula-1a.
A round bottom flask was charged with compound of formula-10 (100 g), ethyl acetate (400
mL) and palladium hydroxide (2.5 g). The reaction mass was stirred under hydrogen gas
pressure 5-6 kg /cm2 for 2 hr at 25-35°C. The reaction mixture was filtered through hyflow,
30 washed with ethyl acetate (25 mL). The filtrate solution was charged with carbon (5 g),
17
stirred for 15 min and filtered the mass through hyflow bed and washed with ethyl acetate
(25 mL). The filtrate solution was taken in other round bottom flask and added glyoxal
solution (45 g, 40%), water (200 mL) stirred for 2 hr at 25-35°C. The reaction mixture pH
was adjusted to 0.5-1.5 with dil HCl (110 mL) and separated the layers. The aqueous layer
was extracted with ethyl acetate (2x100 mL). The combined organic 5 layer was washed with
water (100 mL), brine solution (100 mL), distilled off the solvent completely and co distilled
with methanol (25 mL).
The crude compound was charged with methanol (400 mL), sodium carbonate solution (45 g
in 250 mL of water) and heated to 60-70°C for 3 hr. The reaction mixture was distilled off
10 completely, co distilled with dichloromethane (25 mL). The aqueous layer was washed with
dichloromethane (300 mL) to remove organic impurities. The aqueous layer pH was adjusted
to 10-12 with sodium hydroxide (10 g in 100 mL water), extracted with ethyl acetate (6x100
mL). The combined organic layer was washed with brine solution (100 mL) and dried over
sodium sulphate, charged with carbon (5 g) stirred for 15 min. Filtered the reaction mixture
15 through hyflow bed, washed with dichloromethane (25 mL) and distilled off the solvent
completely and co-distilled with methanol (25 mL). The crude compound was cooled to 25-
35°C, charged with methanol (225 mL), water (9 mL), carbon (5 g) and stirred for 10 min at
same temperature. Filtered the reaction mixture through hyflow bed and wash with methanol
(25 mL). The filtrate solution was added, to a solution of tartaric acid (23.45 g) in methanol
20 (225 mL) at 15-25°C for 2 hr and stirred for 4 hr. Filtered the obtained solid and washed with
methanol (50 mL) and dried to get the title compound.
Yield: 42.16 g.
Example-5: Preparation of the compound of formula-1.
A round bottom flask was charged with compound of formula-1a (75.0 g), water (375 mL)
25 and stirred for 10 min. The reaction mixture pH was adjusted to 11-13 with sodium
hydroxide solution (37.5 g in 75 mL of water) and charged with dichloromethane (375 mL),
stirred for 10 min, layers were separated, the aqueous layer was extracted with dichloro
methane (2x75 mL). The combined organic layer was washed with brine solution (75 mL)
and charged with carbon (7.5 g) to organic layer stirred for 10 min, filtered the organic layer
30 through hyflow bed washed with dichloromethane (75 mL) and distilled off completely, co18
distilled with methanol (18.75 mL). The crude compound was charged with methanol (300
mL) stirred for 10 min at 25-35°C. Filtered the solution through hyflow bed and washed with
methanol (18.75 mL). The organic layer was added, to a solution of tartaric acid (32.25 g) in
methanol (300 mL) at 15-25°C for 0.5 hr and stirred for 10 hr. Filtered the obtained solid and
washed with methanol (75 mL) and dried to 5 get the title compound.
Yield: 68.56 g.
Example-6: Preparation of the compound of formula-8.
A round bottom flask was charged with compound of formula-7 (100.0 g), dichloromethane
(500 mL) and stirred for 10 min. The reaction mixture was cooled to -5 to 5°C added chloro
10 ethylchloroformate (114.05 g) and stirred for 2-3 hr at 25-35°C. The reaction mixture was
distilled off completely, charged with methanol (200 mL) and heated to 60-65°C stirred for 5-
6 hr. The reaction mixture was distilled off completely, cooled to 25-35°C and charged
acetone (100 mL) stirred for 10 min. The reaction mixture further cooled to 5 to 15°C,
filtered the obtained solid and washed with acetone (50 mL) and dried to get the title
15 compound.
Yield: 28.0 g ,CLAIMS:We claims:
1. A process for the preparation of compound of formula-1
5 Formula-1
comprising of:
a)Reacting compound of formula-2
Formula-2
10 with compound of formula-3
Formula-3
in presence of magnesium, in suitable solvent to provide compound of formula-4,
15 Formula-4
b)oxidising the compound obtained in step-a) with suitable reagent, solvent to provide
compound of formula-5,
Formula-5
20 c)reacting the compound obtained in step-b) with suitable reagent, solvent in presence of
phase transfer catalyst to provide compound of formula-6,
Formula-6
20
further reacting the compound of formula-6 in-situ with benzylamine in presence of sodium
borohydride to provide compound of formula-7,
Formula-7
5
d)debenzylating the compound obtained in step-c) in presence of suitable reagent, solvent to
provide compound of formula-8 or free base,
HCl
Formula-8
e)protecting the compound obtained in step-d) with trifluoroacetic anhydride 10 in presence of
suitable base, solvent to provide compound of formula-9, further reacting the compound of
formula-9 in-situ with nitration mixture to provide compound of formula-10,
15 Formula-10
f)reducing the compound obtained in step-e) with palladium catalyst under hydrogen gas
atmosphere in suitable solvent to provide compound of formula-11, further reacting the
compound of formula-11 in-situ with glyoxal solution in water to provide compound of
formula-12,
20
Formula-12
g)deprotecting the compound obtained is step-f) with inorganic base in a suitable solvent to
provide compound of formula-13,
25 Formula-13
21
h)treating the compound obtained in step-g) with tartaric acid in a suitable solvent to obtain
compound of formula-1 or 1a.
Formula-1a
i)optionally purifying the compound obtained in step-h) with suitable base 5 in suitable solvent
to provide varenicline, further converting to tartrate salt of compound of formula-1.
2. The process according to claim 1 wherein in step-a) the suitable solvent is selected from
chloro solvents, ether solvents, or any mixture thereof; preferably : tetrahydrofuran, ether;
wherein in step-b) the suitable solvent is selected from chloro solvents, ether solvents,
10 ketone solvents, ester solvents or any mixture thereof; preferably acetone; the suitable
oxidising agent is osmium tetroxide; other reagent is N-methylmorpholine N-oxide in
butanol solution;
wherein in step-c) the suitable reagent is sodium periodate; the suitable phase transfer
catalyst is selected from triethylbenzyl ammonium chloride, tetrabutylammoniumbromide,
15 tetrabutyl ammonium chloride, tetrabutyl ammonium acetate, methyltributyl ammonium
chloride, tetrabutyl ammonium hydroxide, tributyl benzyl ammonium chloride; the suitable
solvent is selected from chloro solvents, ether solvents, polar aprotic solvents, ester solvents
or any mixture thereof; preferably dichloromethane;
the suitable regents for cyclisation is benzylamine; reducing agent is sodium borohydride,
20 triacetoxy sodiumborohydride;
wherein in step-d) the suitable solvent is selected from chloro solvents, ether solvents, polar
aprotic solvents, polar solvents, alcoholic solvents, ester solvents, Con.HCl or any mixture
thereof; preferably methanolic HCl; the suitable palladium catalyst is selected from Pd(OH)2,
Pd[P(PPh3)]4 , PdCl2, Pd/C; Preferably Pd(OH)2, Pd/C;
25 Optionally the other suitable reagent for debenzylation is ethylchloroformate, methyl chloro
formate, chloroethyl chloro formate; suitable solvents is selected from toluene, benzene,
xylene, methanol, ethanol;
22
wherein in step-e) the suitable solvent is selected from chloro solvents, ether solvents, polar
aprotic solvents, ester solvents, or any mixture thereof; preferably dichloromethane; the
suitable base is selected from organic bases, inorganic base; preferably triethylamine;
protecting agent is trifluoroacetic anhydride; the suitable nitration mixture is trifluoro
methane sulphonic acid, nitric acid or Sulfuric 5 acid, nitric acid;
wherein in step-f) the suitable solvent is selected from chloro solvents, ether solvents, polar
aprotic solvents, ester solvents, alcohol or any mixture thereof; preferably ethyl acetate;
the suitable palladium catalyst is selected from Pd(OH)2, Pd[P(PPh3)]4 , PdCl2, Pd/C;
Preferably Pd(OH)2, Pd/C;
10 wherein in step-g) the suitable solvent is selected from chloro solvents, ether solvents, polar
aprotic solvents, ester solvents, alcohol or any mixture thereof; preferably methanol;
The suitable base is inorganic base; preferably sodium carbonate;
wherein in step-h) the suitable solvent is selected from chloro solvents, ether solvents, polar
aprotic solvents, ester solvents, alcohol or any mixture thereof; preferably methanol;
15 wherein in step-i) the suitable solvent is selected from chloro solvents, ether solvents, polar
aprotic solvents, ester solvents, alcohol or any mixture thereof; preferably dichloromethane,
methanol; the suitable base is selected from inorganic base; preferably sodium hydroxide;
3.A process for the preparation of the compound of formula-1,
20
Formula-1
comprising of:
a)reacting compound of formula-2
25 Formula-2
with compound of formula-3
23
Formula-3
in presence of magnesium in tetrahydrofuran to provide compound of formula-4,
5 Formula-4
b)oxidising the compound obtained in step-a) with osmium tetroxide, in presence of
butanolic solution of N-methylmorpholine N-oxide, in acetone to provide compound of
formula -5,
10 Formula-5
c)reacting the compound obtained in step-b) with sodium periodate in presence of triethyl
benzyl ammonium chloride in dichloromethane to provide compound of formula-6,
Formula-6
15 further reacting the compound of formula-6 in situ with benzylamine in presence of sodium
borohydride, acetic acid to provide compound of formula-7,
Formula-7
d)debenzylating the compound obtained in step-c) in presence of palladium hydroxide in
20 methanolic HCl to provide compound of formula-8,
Formula-8
24
e)protecting the compound obtained in step-d) with trifluoroacetic anhydride in presence of
triethylamine in dichloromethane to provide compound of formula-9, further reacting the
compound of formula-9 in situ with nitric acid in trifluoromethane sulfonic acid, to provide
compound of formula-10 (or) optionally isolating compound of formula-9 reacting with
nitricacid in trifluoromethane sulfonic acid to provide compound 5 of formula-10,
Formula-10
f)reducing the compound obtained in step-e) with palladium hydroxide catalyst under
hydrogen gas atmosphere in ethyl acetate to provide compound of formula-11, further
10 reacting the compound of formula-11 in situ with glyoxal solution in water to provide
compound of formula-12,
Formula-12
g)deprotecting the compound obtained is step-f) with sodium carbonate in methanol to
15 provide compound of formula-13,
Formula-13
h)treating the compound obtained in step-g) with tartaric acid in methanol to provide
20 compound of formula-1 or 1a.
Formula-1a
25
4. A process for the preparation of the compound of formula-1 (one pot process)
Formula-1
5 Comprising of:
a)reducing the compound of formula-10 with palladium hydroxide catalyst under hydrogen
gas atmosphere in ethyl acetate to provide compound of formula-11, further reacting the
compound of formula-11 in-situ with glyoxal solution in water to provide compound of
formula-12,
10
Formula-12
b)deprotecting the compound obtained is step-a) with sodium carbonate in methanol to
provide compound of formula-13,
15 Formula-13
c)treating the compound obtained in step-b) with tartaric acid in methanol to provide
compound of formula-1 or 1a.
Formula-1a
20
26
5. A process for the preparation of the compound of formula-8
HCl
Formula-8
Comprising of
a)reacting the compound of formula-5 with sodiumperiodate in presence 5 of triethyl benzyl
ammonium chloride in dichloromethane to provide compound of formula-6,
Formula-6
further reacting the compound of formula-6 in-situ with benzylamine in presence of sodium
10 borohydride to provide compound of formula-7,
Formula-7
b)debenzylating the compound obtained in step-a) in presence of palladium hydroxide in
methanolic HCl to provide compound of formula-8.
15 HCl
Formula-8
6. A process for the preparation of compound of formula-8 comprising of reacting the
compound of formula-7 with ethylchloroformate in suitable solvents, temperature.
7. The process according to claim 6 the suitable solvents are toluene, xylene, benzene, THF,
20 methanol, ethanol and mixture thereof; suitable temperature is 20-100°C.
8. A process for the preparation of compound of formula-10.
25 Formula-10
27
Comprising of;
a)protecting the compound of formula-8 with trifluoroacetic anhydride in presence of tri
ethylamine in dichloromethane to provide compound of formula-9, further reacting the
compound of formula-9 in situ with nitricacid in trifluoromethane sulfonic 5 acid to provide
compound of formula-10 (or) optionally isolating compound of formula-9 reacting with
nitricacid in trifluoromethane sulfonic acid to provide compound of formula-10.
10 Formula-10
9. The crystalline form-B of varenicline tatrate obtained any of the proceeding claims.
10. Varenicline or varenicline tartrate salt obtained by any of the proceeding claims.